Funded by the National Cancer Institute, investigators with the UCLA Department of Radiation Oncology at UCLA's Jonsson Comprehensive Cancer Center have discovered that the metabolic state of glioma stem cells, which instigate deadly glioblastomas, is considerably different from the metabolic state of brain cancer cells which the glioma stem cells created, a factor which assists these stem cells avoid treatment and cause recurrence later.

The investigation is published this week in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.

They also discovered for the first time that these glioma stem cells can alter their metabolic state at will, from glycolysis, which uses glucose, to oxidative phosphorylation, which uses oxygen.

Dr. Frank Pajonk, an associate professor of radiation oncology and senior author of the investigation explained:

"The glioma stem cells' ability to change their metabolic state at will also allow these stem cells that seed new cancer growth to evade treatment and remain alive.

We found these cancer stem cells are substantially different in their metabolic states than the differentiated cancer cells they create, and since they act differently, they can't be killed in the same way. And as yet, we don't have anything to target these glioma stem cells specifically."

Cancer cells absorb considerable amounts of glucose, which increases their growth and spread rate, allowing them to be differentiated from normal cells under Positron Emission Tomography (PET) scanning, which records metabolic activity. Pajonk and his team discovered less glucose was absorbed in glioma stem cells, making them hard to detect with PET.

In recent years new interest has been gained for targeting cancer metabolic pathways as a treatment. However, treatments may be avoided by cancer cells that take up less glucose by utilizing glucose more efficiently through oxidative phosphorylation, which would not be targeted by such drugs.

The investigation states:

"If glioma stem cells are indeed important for tumor control, knowledge of the metabolic state of glioma stem cells is needed."

A unique imaging system that relies on low enzymatic activity of the proteasome in cancer stem cells which was developed by Pajonk and his team, was used to assess them for metabolic function, including oxygen consumption rates, glucose uptake and other markers. An additional roadblock for targeting these cells with conventional treatments arose when the researchers discovered that the glioma stem cells were resistant to radiation.

Pajonk and his team concluded that for energy, glioma stem cells rely mostly on oxidative phosporylation and discovered that if they stem cells were challenged, they could switch on additional metabolic pathways.

The investigation also reveals for this first time that low expression of proteasome sub-units, an indicator for large number of glioma stem cells in the tumor, predicts unfavorable treatment outcomes for those patients.

Pajonk, who also is an investigator with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, said:

"What I think is really exciting is we have here for the first time a novel cancer stem cell marker in glioma, which gives us an additional tool to look for these cells and come up with therapies that target them."

Grace Rattue

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